Progenitor cells are immature cell types that are responsible for constructing the entire organism during embryonic development as well as for replenishing and repairing tissues in adult life. Understanding progenitor cells is therefore a central question in biology. This problem applies to the pancreas, an organ of vital importance to human physiology because of the production of digestive enzymes and hormones such as insulin. The long term goal of this project is to understand the diversity and development of pancreatic progenitor cells in order to devise better strategies to treat pancreatic diseases such as diabetes. In Specific Aim I of this proposal, we will determine the diversity of progenitor cells in the developing pancreas by a genome scale expression analysis to identify unique molecular markers that will mark each progenitor population. In Specific Aim II, we will determine the lineage of two specific pancreatic progenitor populations by genetic lineage tracing experiments with mutant mouse lines. In Specific Aim III,we will functionally test hypotheses of how transcription factors regulate the development of different progenitor cell types. The proposed studies are expected to shed important light on the diversity and specification of pancreatic progenitor cells. A better understanding of the biology of pancreatic progenitor cells should aid efforts to derive functional endocrine cells for cell replacement therapies to treat diabetes. In addition, these studies may lead to greater insights into adult pancreatic progenitors that may be exploited for regeneration based therapy.